TARGETING HUMAN MITOCHONDRIAL ClpP: A THRILLING CHALLENGE FOR NEW THERAPEUTIC STRATEGIES IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA

Paediatric high-grade gliomas are a devastating subset of brain tumours characterized by their dismal prognosis and no effective available treatment. Among these, H3K27-altered diffuse midline gliomas (DMG) are the most frequently diagnosed. Current standard therapy is limited to radiotherapy (RT), which provides only a temporary clinical response, extending survival by approximately 3 months. To date, DMG remains an incurable disease associated with drug resistance, high recurrence rates, and a median overall survival of less than 12 months [1]. Recent clinical studies confirmed the safety and tolerability of ONC201 in paediatric patients with H3K27-altered DMG [2]. ONC201 exerts its antitumor effect as an activator of the enzyme ClpP, a mitochondrial serine protease involved in protein quality control and metabolic regulation. ClpP and ClpX are degraders of key components of the mitochondrial respiratory chain, leading to mitochondrial dysfunction and tumour cell death. This vulnerability is particularly relevant in cancers that heavily rely on mitochondrial metabolism, making ClpP hyperactivation an attractive antitumor target (Figure 1) [3]. However, worldwide, very few children with DMG have benefited from ONC201 treatment, making it imperative to try to identify potential and effective drugs [4]. Then, using ClpP as a target and ONC201 chemical structure as a “hit”, a series of new compounds have been developed. They demonstrate enhanced ClpP proteolytic activity and a high impact on mitochondrial functionality. The synthesis and bio-pharmaceutical evaluation of these new ONC201 derivatives, as putative candidate drugs for treating DMG, will be described.